This application is a revised version of the previously reviewed grant, AG12834. Insulin resistance and diabetes are the source of considerable health and financial burden for our elderly population. Recent estimates show that the direct medical costs of diabetes and its related disorders climbed from $44 billion in 1997 to almost $92 billion in 2002. Consequently, the search for effective treatment or prevention modalities is a high priority in public health care policy. Although diet and exercise improve insulin sensitivity, it is still entirely unclear as to what regimen of diet composition and exercise is most effective in reversing insulin resistance in the elderly. The proposed research will involve the prospective study of 80 older (65-85 years), obese (BMI = 30-40 kg/m 2) men and women. The central hypothesis is that a low-glycemic diet, combined with aerobic exercise and nutrition counseling reduces insulin resistance in older obese men and women. The specific aims are, I: Identify the effects of high- and low-glycemic diet and exercise interventions on insulin resistance in obese elderly. II: Ascertain which components of body composition are regulated by high- and low-glycemic diet-exercise interventions. III: Establish which insulin signaling proteins in skeletal muscle regulate the change in insulin resistance in response to high- and low-glycemic diet-exercise interventions. The approach includes a 3-week diet/weight stabilization period during which all subjects will be fed a weight-maintenance typical American diet. Subjects will be randomized to receive either a eucaloric high-glycemic diet (approximaely 90 U), or a eucaloric low-glycemic diet (approximately 55 U). All meals will be prepared in the General Clinical Research Center Metabolic Kitchen. Subjects will participate in a 12-week supervised aerobic exercise program and nutrition counseling. Baseline physiological and metabolic testing will include measures of insulin resistance (euglycemic-hyperinsulinemic clamps), substrate oxidation, total and abdominal fat (hydrostatic weighing and computer tomography), lipids, and cytokines. Muscle biopsies will be obtained to measure expression, phosphorylation and activity of proteins in the insulin-signaling pathway. Myocellular lipid content will be determined by proton-nuclear magnetic spectroscopy. Upon treatment completion, all subjects will remain on their respective diet, maintain weight stability and repeat all baseline testing to determine the study outcome effects. It is our expectation that the approach used in this study will identify a more favorable diet-exercise treatment for insulin resistance, as well as the cellular and metabolic mediators that regulate obesity-related insulin resistance in the elderly. These results will be significant, in that they will provide a preventative and therapeutic intervention that will substantially improve the health and quality of life for the growing number of elderly who have developed, or will develop insulin resistance, or diabetes.